Pomegranate peel and ellagic acid attenuate ulcerative colitis by targeting AKR1B1/B3 to inhibit NLRP3

Background Ulcerative colitis (UC) therapy remains challenging due to limited options. Pomegranate peel, rich in bioactive compounds, shows potential, but its key components and mechanisms underlying its action against UC are unclear. Purpose The present investigation was undertaken to assess the therapeutic efficacy of 70 % ethanolic (PPEE) and aqueous extracts (PPWE) derived from pomegranate peel, determine the primary active component, and clarify the underlying molecular mechanism. Study design and methods The anti-UC effects of PPEE and PPWE extracts were first assessed in DSS-induced mice. Differential constituents underlying their efficacy disparities were identified using LC-MS/UHPLC and chemometric analyses. Key bioactive compounds were screened via a model of Caco-2/THP-1 co-culture evaluating intestinal barrier function. The action mechanisms were further elucidated through molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation (Co-IP), and other assays, validated across inflammatory cell models, DSS-induced mice, and human UC colon tissues. Results PPEE showed superior efficacy over PPWE, as evidenced by enhanced intestinal barrier function and suppressed inflammation and NLRP3 inflammasome activation. Ellagic acid (EA) was identified as the core active constituent, which directly targeted AKR1B1/AKR1B3, thereby inhibiting NLRP3-ASC oligomerization and subsequent cleavage of caspase-1 and IL-1 β . Conclusion This study unveils a novel pathogenic mechanism in UC, namely the AKR1B1/AKR1B3-NLRP3 axis, and identifies EA as its effective inhibitor. These results demonstrate the potential of pomegranate peel extracts and offer a novel therapeutic approach for UC.